proteostatis

Proteostasis, sometimes referred to as proteostatis in the literature, denotes the collection of cellular processes that govern the biogenesis, folding, trafficking, maintenance, and turnover of proteins to preserve cellular protein homeostasis. It encompasses the production of proteins, their correct folding, trafficking to appropriate cellular compartments, and the timely removal of misfolded or damaged species.

A core proteostasis network includes molecular chaperones such as Hsp70, Hsp90, and small heat shock proteins, folding enzymes, components of the ubiquitin–proteasome system, and autophagy–lysosome pathways. Quality-control mechanisms operate in multiple cellular locales, including the cytosol and the endoplasmic reticulum, where misfolded proteins are detected and directed toward refolding or clearance.

Key pathways involved are chaperone-assisted folding, the ubiquitin-proteasome system for targeted degradation of damaged proteins, and autophagy for the clearance of larger aggregates and organelles. The unfolded protein response and other stress signaling pathways help cells adapt to proteostatic stress by upregulating chaperones and adjusting degradation and synthesis rates.

Regulation of proteostasis involves several signaling networks. The heat shock response, mediated by HSF1, increases chaperone production. In the ER, the unfolded protein response involves sensors such as IRE1, PERK, and ATF6, coordinating transcriptional and translational programs. Nutrient and energy status influence autophagy through mTOR and AMPK signaling, integrating proteostasis with cellular metabolism.

Proteostatic maintenance is essential for development and health and declines with age. Failures in proteostasis are linked to neurodegenerative diseases, aging, and certain cancers. Research aims to modulate proteostasis by boosting chaperone capacity, enhancing degradation pathways, or stimulating autophagy as therapeutic strategies.